Thrombophilia in sickle cell disease: the red cell connection

Complex pertubations of hemostasis occur in sickle cell disease (SCD). Alth ough the procoagulant property of sickle erythrocytes in vitro is tied to e xposure of phosphatidylserine (PS), no study has directly linked this PS po sitivity to in vivo thrombin generation. This study was designed to determi ne if thrombin generation in SCD correlates with erythrocyte PS, or whether platelets play a significant role. PS was quantified on erythrocytes and p latelets from 40 patients with SCD (SS genotype = 25; SC genotype = 15) and 11 controls. Markers of thrombin generation (prothrombin fragment F1.2; th rombin-antithrombin or TAT complexes) and fibrin dissolution (D-dimer; plas min-antiplasmin or PAP complexes) were also evaluated. Thrombin generation and activation of fibrinolysis occurred with elevations in F1.2, TAT, and D -dimer. Although numbers of both PS-positive erythrocytes and platelets wer e elevated, there was no correlation between PS-positive platelets and any hemostatic markers. In contrast, correlations were noted between PS-positiv e erythrocytes and F1.2 (P < .0002), D-dimer (P < .000002), and PAP (P < .0 1). Correlations between F1.2 and D-dimer (P < .0001) demonstrated that fib rinolysis was secondary to thrombin generation. In patients with the SC gen otype, abnormalities in coagulation, although present, were of a lesser mag nitude than in SS disease. This study suggests that the sickle erythrocyte is the cell responsible for the thrombophilic state in SCD because associat ions between erythrocyte PS and thrombin generation were observed. No such relationship with platelet PS was noted. The use of erythrocyte PS as a sur rogate marker in trials testing new therapeutic modalities may provide insi ghts into the vascular complications of SCD. (Blood. 2001; 98:3228-3233) (C ) 2001 by The American Society of Hematology.